Combinations of opioid/tlr4 antagonist and acetyl-para-aminophenol (apap) for use in the reduction of toll-like receptor 4(tlr4) and cyclooxygenase-2 (cox-2) activity

ABSTRACT

Disclosed are compositions for the treatment of pain comprising a first compound and a second compound, the first compound is an opioid antagonist that treats pain by blocking Toll-like receptor 4 (TLR4) and the second compound is acetyl-para-aminophenol (APAP) that enhances the pain treatment effect of the first compound. Examples of opioid antagonist include naltrexone and naloxone, synergistic pharmaceutical compositions thereof, and their use in the treatment, prevention, and reversal of neuropathic and nociceptive pain.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/812,698 filed Jul. 29, 2015, which is a divisional of U.S.application Ser. No. 13/837,099 filed Mar. 15, 2013, the entireteachings of which are incorporated herein by reference.

FIELD OF INVENTION

This invention relates to combinations of an opioid/TLR4 antagonist andacetyl-para-aminophenol (APAP) particularly those that exhibit asynergistic effect for the treatment, prevention and reversal of pain.

BACKGROUND

It is well established in medical literature that treatments currentlyavailable for pain have limitations. Opioid drugs cause tolerance,dependence and side effects sufficiently serious to prompt recent actionby the FDA to further restrict the drugs. Newly approved treatments,like the calcium channel alpha-2-delta ligands gabapentin and pregabalinand the serotonin and norepinephrine reuptake inhibitors milnacipran andduloxetine, require high doses to show nominal effectiveness, have ahigh dropout rate and carry many side effects.

This invention is a novel approach for the treatment of pain. It isdirected to the treatment of neuropathic and nociceptive pain. Onecomponent of the combination is directed to reducing neuropathic painand the allodynic component associated with nociceptive pain and theother component address nociceptive pain. Specific combination of drugsand the dosage needed to create that effect is the subject of theinstant invention.

The unifying theory explaining neuropathic pain is the understandingthat TLR4 are activated endogenously and trigger a pro-inflammatorycascade. That cascade is interrupted and in most cases eliminated bytreatment using the systemic administration of an opioid/TLR4antagonist, particularly naltrexone, or a pharmaceutically acceptablesalt thereof.

Acetyl-para-aminophenol (APAP) enhances the pain relief action of theopioid/TLR4 antagonist naltrexone. A specific synergistic dose range ofthe combination is herein presented.

In a dose finding study the combination of the opioid/TLR4 antagonist,naltrexone and acetyl-para-aminophenol (APAP), acted synergistically,whether administered separately, one right after the other, oradministered in combination.

Various μ-opioid receptor ligands have been tested and were found toalso possess action as agonists or antagonists of Toll-like receptor 4(TLR4). Toll-like receptors, found in the glia, are a class of receptorsthat play a key role in the innate immune system. They recognizepathogen-associated molecular patterns (PAMPs) such aslipopolysaccharide (LPS) that are expressed on infectious agents, andmediate the production of cytokines necessary for the development ofeffective immunity. Opioid agonists such as morphine act as TLR4agonists, while opioid antagonists such as naloxone and naltrexone werefound to be TLR4 antagonists. Activation of TLR4 by opioid agonists suchas morphine leads to downstream release of inflammatory modulatorsincluding TNF-α and interleukin-1. Constant low-level release of thesemodulators is thought to reduce the efficacy of opioid drug treatmentwith time and to be involved in both the development of tolerance toopioid analgesic drugs and in the emergence of side effects such ashyperalgesia and allodynia which can become problems following extendeduse of opioid drugs.

Accordingly, the instant invention relates to μ-opioid receptor ligandas ligands of TLR4 as well and contemplates that allodynia is caused byactivation of TLR4. Blockage of TLR4 accordingly will eliminateallodynia.

The best known opioid receptor antagonists are naloxone and naltrexone.Naltrexone is an opioid receptor antagonist used primarily in themanagement of alcohol dependence and opioid dependence. A dose of 50-300mg once daily is recommended for most patients. Naloxone is an opioidinverse agonist: it is a drug used to counter the effects of opiateoverdose.

Low dose naltrexone describes the off label use of naltrexone at dosesless than 10 mg per day for indications other than chemical dependencyor intoxication.

It has been suggested in the literature that low dose naltrexone exertsthe opposite effect of naltrexone in full dose. While the full dosenaltrexone blocks the opiate system, the low dose naltrexone promotesthe production of endorphins by the mechanism of up regulation caused bypartial opiate receptor blockage. The beneficial effect of naltrexonewas attributed to the increase in endorphins. The beneficial effect oflow dose naltrexone can be further explained by its antagonism of TLR4.

Other opioid receptor antagonists used in clinical or scientificpractice that can also be used for the treatment of pain include but arenot limited to the following: naloxone, nalmefene, norbinaltorphimine,nalorphine, methylnaltrexone, samidorphan, cyprodime, naltrindole,amentoflavone, naltriben, norbinaltorphimine, and the naltrexonemetabolite 6-β-naltrexol.

Our understanding of pathological pain has primarily revolved aroundneuronal mechanisms. However, neighboring glia, were TLL4 reside,including astrocytes and microglia; have recently been recognized aspowerful modulators of pain.

Studies show that TLRs can be activated not only by well-known“non-self” molecular signals but also by endogenous signals (IL-1β,TNFα, IL-6 and NO) produced during chronic neuropathic pain states.Fibronectin, an endogenous TLR4 ligand that is produced in response totissue injury, leads to an up regulation of the purinoceptor P2X4, whichis expressed exclusively on microglia.

Several opioid antagonist drugs were found to act as antagonists forTLR4, including naloxone and naltrexone. However it was found that notonly the “normal” (−) enantiomers, but also the “unnatural” (+)enantiomers of these drugs acted as TLR4 antagonists. The unnaturalenantiomers of the opioid antagonists, (+)-naltrexone and (+)-naloxone,dextro-naltrexone and dextro-naloxone, have been discovered to act asselective antagonists of TLR4. Since (+)-naloxone and (+)-naltrexonelack affinity for opioid receptors, they do not block the effects ofopioid analgesic drugs, and so can be used to counteract theTLR4-mediated side effects of opioid agonists without affectinganalgesia. (+)-Naloxone was also found to be neuroprotective, and both(+)-naloxone and (+)-naltrexone are effective in their own right attreating symptoms of neuropathic pain in animal models.

Acetyl-para-aminophenol (APAP) or acetaminophen (used in the UnitedStates Canada, Japan, South Korea, Hong Kong, and Iran) and paracetamol(used elsewhere) both come from a chemical name for the compound:para-acetylaminophenol and para-acetylaminophenol. In some contexts, itis simply abbreviated as APAP, for acetyl-para-aminophenol.Acetyl-para-aminophenol is a widely used over-the-counter analgesic andantipyretic. Acetyl-para-aminophenol is classified as a mild analgesic.It is commonly used for the relief of headaches and other minor achesand pains and is a major ingredient in numerous cold and flu remedies.In combination with opioid analgesics, acetyl-para-aminophenol can alsobe used in the management of more severe pain such as post-surgical painand providing palliative care in advanced cancer patients. Thoughacetyl-para-aminophenol is used to treat inflammatory pain, it is notgenerally classified as an NSAID because it exhibits only weakanti-inflammatory activity.

To date, the mechanism of action of acetyl-para-aminophenol is notcompletely understood. The main mechanism proposed is the inhibition ofcyclooxygenase (COX), and recent findings suggest that it is highlyselective for COX-2. While it has analgesic and antipyretic propertiescomparable to those of aspirin or other NSAIDs, its peripheralanti-inflammatory activity is usually limited by several factors, one ofwhich is the high level of peroxides present in inflammatory lesions.However, in some circumstances, even peripheral anti-inflammatoryactivity comparable to NSAIDs can be observed.

Acetyl-para-aminophenol enhances the pain treatment effect of naltrexoneby affecting nociceptive pain.

Nociceptive pain is caused by stimulation of peripheral nerve fibersthat respond only to stimuli approaching or exceeding harmful intensity(nociceptors), and may be classified according to the mode of noxiousstimulation. Deep somatic pain is initiated by stimulation ofnociceptors in ligaments, tendons, bones, blood vessels, fasciae andmuscles, and is dull, aching, poorly localized pain. Examples includesprains and broken bones.

Allodynia is a clinical feature of many painful conditions, such as backpain, chronic pain, neuropathic pain, diabetic neuropathic pain,trigeminal neuralgia pain, phantom limb pain, complex regional painsyndrome pain, acute herpetic pain, post herpetic pain, causalgia pain,idiopathic pain, inflammatory pain, cancer pain, postoperative pain,fibromyalgia pain, headache pain, migraine pain, allodynia pain,vulvodynia pain, interstitial cystitis pain, irritable bowel syndrome(IBS), arthritic joint pain and tendinitis. It becomes apparent thatallodynia plays a role in every kind of pain.

The unifying theory of allodynia, or “memory pain”, as allodynia may bedescribed in lay terms, is the understanding that TLR4 are activatedendogenously and trigger a pro-inflammatory cascade. That cascade isinterrupted by the opioid/TLR4 antagonist drugs as claimed by theinstant invention. Additionally, TLR4 antagonism can play a role inimproving nociceptive pain as well by affecting the allodynic componentof nociceptive pain.

Based upon this, the instant invention first teaches the use of anopioid/TLR4 antagonist, particularly naltrexone for its antagonism ofthe TLR4 and blocking release of inflammatory modulators. Secondly, theinvention teaches use of acetyl-para-aminophenol, for its action onnociception and its anti-inflammatory action. The invention teaches thatthe combination is synergy as far as the effect on pain treatment.

The invention contemplates several forms of opioid antagonist selectedfrom a group consisting of naltrexone, naloxone, nalmefene,norbinaltorphimine, nalorphine, methylnaltrexone, samidorphan,cyprodime, naltrindole, amentoflavone, naltriben, norbinaltorphimine,and metabolite 6-β-naltrexol and metabolites and pro drugs thereof,including all enantiomeric and epimeric forms as well as the appropriatemixtures thereof, or pharmaceutically acceptable salts or solvates ofany thereof.

SUMMARY OF INVENTION

The instant invention is a synergistic combination product comprising afirst compound and a second compound, where the first compound is anopioid antagonist that treats neuropathic pain by blocking receptor TLR4and the second compound is a acetyl-para-aminophenol that treatsnociceptive pain possibly by highly selective inhibition forcyclooxygenase 2 (COX-2). It enhances the pain treatment effect of thefirst compound. Another invention embodiment is a method for thetreatment, prevention, and reversal of pain, neuropathic as well asnociceptive pain.

DESCRIPTION OF EMBODIMENTS

This invention provides a combination, comprising an opioid/TLR4antagonist and acetyl-para-aminophenol, and pharmaceutically acceptablesalts or solvate of any thereof.

Another invention embodiment is a combination, comprising an opioidantagonist and acetyl-para-aminophenol. The opioid/TLR4 antagonist isselected from a group consisting of naltrexone, norbinaltorphimine,nalmefene, naloxone, nalorphine, methylnaltrexone, samidorphan,cyprodime, naltrindole, amentoflavone, naltriben, norbinaltorphimine,6-β-naltrexol and metabolites thereof, including all enantiomeric andepimeric forms as well as the appropriate mixtures thereof, as well aspro drugs or metabolites thereof or pharmaceutically acceptable salts orsolvates of any thereof.

Another invention embodiment is a combination, comprising an opioidantagonist and acetyl-para-aminophenol, the opioid antagonist/TLR4 isnaltrexone as well as pro drugs and all enantiomeric and epimeric forms,specifically, (+)-naltrexone (dextro-naltrexone), as well as theappropriate mixtures thereof, or pharmaceutically acceptable salts orsolvates of any thereof.

Another invention embodiment is a combination, comprising an opioidantagonist and acetyl-para-aminophenol, the opioid antagonist/TLR4 isnaltrexone in a sustained release formulation, as well as pro drugsthereof or any enantiomeric and epimeric forms thereof, as well as theappropriate mixtures thereof, or pharmaceutically acceptable salts orsolvates of any thereof.

Another invention embodiment is a combination, comprising an opioidantagonist and acetyl-para-aminophenol, the opioid antagonist/TLR4 is(+)-naltrexone (dextro-naltrexone), as well as pro drugs thereof or anyenantiomeric and epimeric forms thereof, as well as the appropriatemixtures thereof, or pharmaceutically acceptable salts or solvates ofany thereof.

Another invention embodiment is a combination, comprising naltrexone, ora pharmaceutically acceptable salt or solvate thereof, andacetyl-para-aminophenol, or a pharmaceutically acceptable salt orsolvate thereof.

Another invention embodiment is a combination, comprising naltrexone andacetyl-para-aminophenol in a weight to weight combination range whichcorresponds to a synergistic combination range of the order of 2.25:325parts by weight.

Another invention embodiment is a combination, comprising the dose rangeof naltrexone, or a pharmaceutically acceptable salt or solvate thereof,is about 0.004 mg/kg-0.71 mg/kg per day.

Another invention embodiment is a combination, comprising the dose rangeof acetyl-para-aminophenol, or a pharmaceutically acceptable salt orsolvate thereof, is about 5 mg/kg-57 mg/kg per day.

Another invention embodiment is a combination, comprising the human doserange of naltrexone, or a pharmaceutically acceptable salt or solvatethereof, is 0.25 mg-50 mg per day.

Another invention embodiment is a combination, comprising the human doserange of naltrexone, or a pharmaceutically acceptable salt or solvatethereof, is 0.25 mg-25 mg per day.

Another invention embodiment is a combination, comprising the human doserange of naltrexone, or a pharmaceutically acceptable salt or solvatethereof, is 0.25mg -15 mg per day.

Another invention embodiment is a combination, comprising the human thedose range of acetyl-para-aminophenol, or a pharmaceutically acceptablesalt or solvate thereof, is 324 mg-4000 mg.

Another invention embodiment, is a combination, comprising the humandose range of naltrexone, or a pharmaceutically acceptable salt orsolvate thereof, is 0.25 mg-50 mg per day, and the human the dose rangeof acetyl-para-aminophenol or a pharmaceutically acceptable salt orsolvate thereof, is 324 mg-4000 mg, wherein said composition isformulated into a single fixed combination dosage form.

Another invention embodiment, comprising the composition is administeredonce, twice, three or four times through the day.

Another invention embodiment, comprising the therapeutically effectivedose of the pharmaceutical composition is administered systemically bysuch routes including but are not limited to mucosal, nasal, oral,parenteral, gastrointestinal, topical or sublingual routes.

Another invention embodiment comprising, said combination is in a singledosage form, and said single dosage form is in the form of tablets,lozenges, troches, hard candies, liquid, powders, sprays, creams, salvesand suppositories.

Another invention embodiment, the pharmaceutical composition is used forthe treatment, prevention and reversal of neuropathic pain andinflammatory nociceptive pain, such as inflammatory arthritic pain,rheumatoid arthritis, back pain, chronic pain, diabetic neuropathicpain, trigeminal neuralgia pain, phantom limb pain, complex regionalpain syndrome pain, acute herpetic pain, post herpetic pain, causalgiapain, idiopathic pain, inflammatory pain, cancer pain, postoperativepain, fibromyalgia pain, headache pain, migraine pain, allodynia pain,vulvodynia pain, interstitial cystitis pain, irritable bowel syndrome(IBS), arthritic joint pain and tendinitis.

In another invention embodiment the pharmaceutical composition is usedfor the treatment, prevention and reversal of pain wherein said pain isback pain.

In another invention embodiment the pharmaceutical composition is usedfor the treatment, prevention and reversal of pain wherein said pain isneuropathic pain.

In another invention embodiment, the pharmaceutical composition is usedfor the treatment, prevention and reversal of pain wherein said pain ismigraine headache.

In another invention embodiment, the pharmaceutical composition is usedfor the treatment, prevention and reversal of pain wherein said pain istrigeminal neuralgia.

In another invention embodiment, the pharmaceutical composition is usedfor the treatment, prevention and reversal of pain wherein said pain isvulvodynia.

In another invention embodiment, the pharmaceutical composition is usedfor the treatment, prevention and reversal of pain wherein said pain isirritable bowel syndrome.

In another invention embodiment, the pharmaceutical composition is usedfor the treatment, prevention and reversal of pain wherein said pain ispost herpetic neuralgia.

In another invention embodiment, the pharmaceutical composition is usedfor the treatment, prevention and reversal of pain wherein said pain isdiabetic neuropathy.

In another invention embodiment, the pharmaceutical composition is usedfor the treatment, prevention and reversal of nociceptive pain with anallodynic component.

In another invention embodiment is a method of treating neuropathic,nociceptive and migraine pain in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of acombination comprising opioid/TLR4 antagonist andacetyl-para-aminophenol, or a pharmaceutically acceptable salt orsolvate thereof.

In another invention embodiment, the combination of naltrexone, or apharmaceutically acceptable salt or solvate thereof, andacetyl-para-amino, or a pharmaceutically acceptable salt solvate thereofmay optionally be administered with one or more other pharmacologicallyactive agents. Appropriate optional agents include: NSAID's e.g.aspirin, ibuprofen, naproxen, naprosyn, diclofenac, ketoprofen,tolmetin, sulindac, mefanamic acid, meclofenamic acid, diflunisal,flufenisal, piroxicam, sudoxicam, isoxicam, celecoxib, fofecoxib,flosulide, meloxicam, 6-methoxy-2-naphthylacetic acid, nabumetone,nimesulide, steroidal anti-inflammatory drugs, tricyclic antidepressants(TCAs), selective serotonin reuptake inhibitors (SSRIs),serotonin-norepinephrine reuptake inhibitors (SNRIs), anticonvulsants,muscle relaxants, drugs with NMDA antagonist properties,tetrahydrocannabinol derivatives, antitussive, expectorants,decongestants, or antihistamines.

In another invention embodiment for non-human animal administration theterm “pharmaceutical” as used herein may be replaced by “veterinary”.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be described more fully hereinafter withreference to the accompanying drawings, in which preferred embodimentsof the invention are shown. This invention may, however, be embodied inmany different forms and should not be construed as limited to theembodiments set forth herein. Rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the invention to those skilled in the art.

Pharmaceutical Composition

Naltrexone and acetyl-para-aminophenol were evaluated alone and incombination on a human subject with the purpose of finding whether ornot a combination of the two compounds offers a synergistic advantagefor the pain treatment effect comparing the amounts used weight toweight.

The components of the combination were administered to a subject asfollows, the naltrexone dose administered by itself was 4.5 mg and theacetyl-para-aminophenol dose administered by itself was 1000 mg, Thenaltrexone/acetyl-para-aminophenol combination dose was 2.25 mg/325respectively. The pain treatment effect of naltrexone andacetyl-para-aminophenol was evaluated one hour post-dose.

To determine synergy, the amounts of naltrexone andacetyl-para-aminophenol administered alone were compared to thecombination combined amounts. For proper weight to weight (W/W)comparison between naltrexone and acetyl-para-aminophenol an adjustmentfor the higher potency of naltrexone was made based on the dose of eachcompound given by itself. Naltrexone is 222 times more potent thanacetyl-para-aminophenol (1000/4.5=222). Naltrexone andacetyl-para-aminophenol were administered at fixed dose ratios of2.25:325 to a human subject afflicted with neuropathic back pain.

illustrates the naltrexone/acetyl-para-aminophenol ratio that exhibitedweight to weight (w/w) synergy in a human subject. The 2.25:325combination represents a 2-fold lower dose of naltrexone and 3-foldlower dose of acetyl-para-aminophenol when administered together.

TABLE 1 Naltrexone/acetyl-para-aminophenol Ratio and Weight to Weight(w/w) Synergy Nal- Total Dose trex- Naltrexone + Acetyl- one AdjustedNal- para- Potency Acetyl-para- trex- amino- Adjust- % amino- one phenolment Reversal phenol Inter- Ratio mg mg (×222) of Pain mg action 4.5:04.50 — 1000 100 1000 —     0:1000 — 1000 —  50 1000 —  2.25:325 2.25 325  500 100 500 + Synergy 325 = 825

To summarize the naltrexone/acetyl-para-aminophenol synergistic effect,the invention teaches that the optimal contemplated naltrexone, or apharmaceutically acceptable salt or solvate thereof, toacetyl-para-aminophenol, combination dosage ratio range is 2.25:325, andthis dosage ratio exhibits synergy of weight to weight proportion.

CITATION LIST

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1.-16. (canceled)
 17. A method of reducing toll-like receptor 4 (TLR4)activity and of cyclooxygenase (COX-2) activity in a mammal byadministering to the mammal an effective amount of naltrexone andacetyl-para-aminophenol (APAP).
 18. The method of claim 17, wherein themethod is performed in a mammal who has activated TLR4.
 19. The methodof claim 18, wherein the activation of TLR4 results in activation of apro-inflammatory cascade.
 20. The method of claim 19, whereinsimultaneous inhibition of TLR4 and COX-2 activation results inreduction of the pro-inflammatory cascade.